Ester of 2-hydroxy-cyclohexane-2-substituted carboxylic acids

ABSTRACT

The invention provides esters of 2-phenyl-2-hydroxy-cyclohexanecarboxylic acid and of 2-cyclohexyl-2 hydroxy-cyclohexanecarboxylic acid, as well as physiologically compatible salts thereof, which esters and salts have a substantial antispastic activity.

United States Patent Turbanti [4s] Oct. 24, 1972 ESTER 0F z-uvrmoxv- CYCLOHEXANE-Z-SUBSTITUTED CARBOXYLIC ACIDS Luigi Turbanti, Via Bonaccorso Da Padule, l0, Pisa, Italy Filed: Sept. 11, 1970 Appl. No.: 71,360

Related US. Application Data Division of Ser. No. 632,563, April 21, 1967, abandoned.

Inventor:

US. Cl. ..260/293.82, 260/247.2 B, 260/293.65, 260/293.73, 260/468 R, 260/473 A,

Int. Cl. ..C07d 29/24 Field of Search 260/2472 B, 268 R, 293.65, 260/293.82, 468 R, 473 R, 473 A References Cited OTHER PUBLICATIONS Morrison et al., Organic Chemistry, 2nd Edition, Allyn and Bacon, lnc., Boston (1966), p. 467. Zimmerman et al., J. Am. Chem. Soc. 76, 2285- 2290 1954).

Primary Examiner-Henry R. Jiles Assistant Examiner-G. Thomas Todd Attorney-Steinberg & Blake [57] ABSTRACT 7 Claims, No Drawings ESTER OF 2-7-I-IYDROXY-CYCLOHEXANE-2i SUBSTITUTED CARBOXYLIC ACIDS REFERENCE TO RELATED APPLICATIONS v This application is a divisional of my copending ap- 5 plication Ser. No. 632,563, filedApr. 21,,1967, for 2- Hydroxycyclohexanecarboxylic-2-Substituted Acids, Basic Esters Thereof and Salts Showing A Choleretic Antispastic Activity, now abandoned. A'separate divisional application Ser. No. 7l,539 was filed on'Sept. 1O

1 l, 1970, directed to the choleretic. activity of-the free acids.

BACKGROUND OF THE INVENTION thereof, which esters have been foundto have asub- 2O stantial antispastic activity. This is most surprising in view of the fact that the free acids do not have any antispastic activity whatsoever but only have a marked choleretic activity. The esters of the present invention,

on the other hand, exhibit a marked antispastic activity without undesired side effects.

SUMMARY OF THE INVENTION Generally speaking, the present invention provides a series of new compounds having a substantial an- 3 tispastic activity, these compounds beingesters of 2- phenyl-2-hydroxy-cyclohexane-carboxylic acid,and of 2-cyclohexyl-2-hydroxy-cyclohexane-carboxylic acid, as well as salts thereof.

It is thus a primary object of the present invention to provide new esters and salts thereof.

It is another object of the present inventiontoprovide a method of producing'these esters as well asthe salts thereof.

It is yet a further object of the present inventionzto 40 I R on wherein R is selected from the group consisting of phenyl and cyclohexyl, and wherein X 1s COO wherein R is selected from the group consisting of CzHa on-cu b: CzHs H: A CIHB and physiologically compatible salts thereof.

Amongthe. suitable physiologically compatible salts of the above basic esters are those with inorganic and organic. acids .such as'hydrochloric acid, sulfuric acid,.

citric acid, malonic. acid, tartaric acid, etc. The invention also includes quaternary compounds of the above basic esters-with-alkyl'halides such as methyl bromide, ethylbromidepropyl bromide, butyl bromide, as well as with methyl-para-toluene-sulfate.

The acids fromwhich the esters of the present invention areformedmay beproduced in several different ways. 7

The compounds ,2-phenyl-2-hydroxyl-cyclohexanecarboxylic acid and,2-cyclohexyl-2-hydroxy-cyclohexane carboxylic acidmay be produced by reaction 2- hydroxy-methyl-cyclohexanone with a Grignard re agentiin ether solution,isolatingthe corresponding alcohol 2.-hydroxyrnethyl-cyclohexan-l-ol from the ether reaction solution by vacuum distillation and oxidizing the latter with mixtures such as permanganate-sodium carbonate, chromicanhydride-acetic acid, chromic anhydride-pyridine, dilute nitric acid, or the like, toobtain the desired acid.

The 2-cyclohexyl compound-may also be produced by reducing 2-phenyl-'Z-hydroxy-cyclohexane carboxylic acid' in an acetic acid solutionin the presence of PtO at .C. and a pressure of 20 atmospheres.

The. basic. esters of 'the' present invention may be prepared by reacting the potassium saltof the corresponding acid in alcoholic solution with an alkyl chloride. selected from the group consisting of 2- dimethyl-aminoethyl chloride, 2-diethylaminoethyl chloride, 2-diethylamino-l-methyl-ethyl chloride, 3- diethylaminopropyl chloride, 2-di-isopropylaminoethyl chloride, 3-diethyl-amino-2-dimethyl-propyl chloride, 3-chloro-N-methyl-piperidine, 3-chloro-N- ethyl-piperidine, 2( N-piperidino)- ethyl chloride, 3(N- morpholino)-2-dimethyl-propyl chloride and N,N' .(2- 'chloro-ethyl)-piperazine, and isolating by vacuum distillationzthe ester formed after separation from the reaction mixture.

Another method of producing the basic esters of the vpresent invention is to transform the corresponding acid into the ester by reacting the potassium salt thereof withithe corresponding alkylene-dihalide' such as l, 2-dibromo-ethane, or 1,3-dibromopropane or 1,2- dibromo-propane, and processing thereof with a secondary amine such as dimethylamine, diethylamine, diisopropylamine, piperidine or piperazine.

, 3 V DESCRIPTION OF PREFERRED EMBODIMENTS EXAMPLEI This Example illustrates the production of the free acid 2-phenyl-2-hydroxy-cyclohexane-carboxylic acid.

25 g. of 2-hydroxy-methyl-cyclohexanone, diluted in 20 cc of ether, were dropped into a vessel containing an ether suspension of phenyl-magnesiunrbromide (prepared from 19.6 g. of magnesium and 128 g. of hromobenzene in 300 cc. of ether according to usual techniques by stirring and external ice-cooling The mixture was stirred for some time, then the magnesium compound was decomposed by pouring it carefully into water and ice; the magnesium hydroxide was dissolved in 50 cc. of a saturated solution of ammonium chloride, the ether portion was separated and the aqueous portion extracted with further ether.

Collected and dried ether extracts were evaporated 1 phenyl-2-hydroxy-ethylene-cyclohexan1l-ol. m.p. (Kofler) 8 l-83 C.

The thus obtained product was dried and finely powdered, andthen suspended in 1.41. of an aqueous solution of 14 g. of KMnO and 7 g. of Na,CO and the suspension was thoroughly stirred for one day.

After filtering off of the MnO thus formed, a small amount of Na SO was added till the violet coloration disappeared; MnO, was filtered again and the alkaline solution was acidified with concentrated HCl.

After 1 day standing in a refrigerator, the product was washed with water and filtered, thus yielding 5 g. of 2-phenyl-2-hydroxy-cyclohexane-carboxylic acid, m.p. (Kofler) l43-l 45 C.

EXAMPLE 2 cyclohexane-carboxylic acid, m.p. (Kofler) l22-l24 The following Examples illustrate the production of the esters of the present invention.

EXAMPLE 3' N-ethyl-3- piperidyl 2-phenyl-2-hydroxy-cyclohexane-carboxylate In general formula (I) X II 000 JHHI hydrochloric solution was twice extracted with ether, I

alkalinized with NaOl-l and the oil formed was extractedwith ether. The dried and evaporated ether extract left an oleous residue which, vacuum distilled, yielded 3.2 g. of N-ethyI-B-piperidyl 2-phenyl-2- hydroxy-cyclohexane-carboxylate as a colorless oil b.p. m ,,,,1s3-15s c.

- EXAMPLE 4 N-ethyl-B-piperidyl 2-phenyl-2-hydroxy-cyclohexanecarboxylate tartrate In general formula (I) x coo coon R 00H:

N H-OH gHr- H-OH EXAMPLE 5 Diethyl-methylarnmonium ethyl iodide 2-phenyl-2-' hydroxy-cyclohexanecarboxylate 1.5 g. of diethylarninoethyl 2-phenyl-2-hydroxycyclohexanecarboxylate and 0.78 g. of methyl iodide were dissolved in 5 cc. of methanol and the solution was heated in a closed vessel at C for 7 days. By

evaporation of the'reaction solution a product was ob- A tained which after washings with ether and crystallizations from isopropanol was in the form of light yellow crystals, mp. 143-l45 C.

By the general methods previously described the following compounds were obtained. l. 2-(N-piperidino)-ethyl cyclohexane-carboxylate Z-phenyl-Z-hydroxy- 7 l5. 2-diethylaminoethyl 2-cyclohexyl-2-hydroxycyclohexane-carboxylate R=C,,1-1

b.p; 169 C; colorless oil.

1 6. 2,2-dimethyl-3-(4-morpholino )-propyl cyclohexyl-2-hydroxy-cyclohexane-carboxylate e 11 i i b.p. 169 C; colorless oil.

17. l-methy1-3-piperidyl 2-cyclohexyl-2-hydroxycyclohexane-carboxylate R C H,

b.p. 185-186 C; yellow oil.

18. 2-( l-piperidino )-ethyl 2-cyclohexyl-2-hydroxycyclohexanecarboxylate R CGHU I b.p. 166167 C; yellowish oil.

l 9. 2-diethylaminoethyl-2-phenyl-2-hydroxycyclohexane-carboxylate l. Diethylaminoethyl 2-phenyl-2-hydroxy-cyclohexane-carboxylate hydrochloride; colorless thick oil with analytic data agreeing with theoretical data.

2. Z-dimethyl-3-triethylammonium-propyl 2-pheny1- 2-hydroxy-cyclohexane-carboxylate' iodide; low

melting,amorphous, resinous solid product.

3. 2-dimethyl-3-diethyl-methylammonium-propyl 2- phenyl-Z-hydroxy-cyclohexane-carboxylate iodide; low melting, amorphous yellow powder.

4. 2-dimethyl-3-diethyLmethylammonium-propyl ptoluene-sulfonate 2-cyclohexyl-2-hydroxycyclohexane-carboxylate; colorless crystals, m.p. -l44 C.

- 5. 2-di-isopropyl-methylammonium-ethyl-ptoluenesulfonate 2-cyclohexyI-2-hydroxycyclohexane-carboxylate; yellow thick oil.

The antispastic activity of the esters and salts was determined on segments of various isolated organs and it could be observed that the products of the invention inhibit or prevent contraction caused by various spasmogen agents both of hormonal and humoral nature, as well as of a different nature; for some of the tested compounds such inhibitory or preventive activity is already apparent at a concentration of 1X10 and 1X10"? 1' The antispastic activity of the compoundsiaccordigg to the invention is better shown in Table 3, wherein, in terms of concentration, the ED inhibiting the spasm of isolated organs are given (guinea pigs terminal ileus, rats ascending colon, rats jajunam, she-rats uterus) produced by some spasmogen agents, such as histamine (Hist), 5-hydroxy-tryptamine (51-11), acetyl choline, and BaCl 1n the table, along with some products according to the invention, there are also given some commercially available antispastics, and the respective values of ED prove that the new ;compounds may be advantageously compared with the latter.

TABLE 3 Products Spasmogens Hist. 5HT Acetyl Bael choline used 0 1 glml 1 glml 0.15 g/ml 2'50 glml LG.30140 4 10' 1.5.10 2 .10" 5. .10' LG.30141 5 .10' 6 .10' 3 .10 7.5 .10 LG.30144 l5 10" 2.5.10 2.5 .10" 2.5 .10 LG.30127 5 .10' 6.10" l .10 1.5 .10 LGJUIZB l. 10* 6 .10 l .10 S .10 Papave- 7.5.10 1 .10 1 .10" 2.5 .10" rine Buscopan l .10 1 .10' 2 .10 1 .10 Spasma- 25.10' 2.5 .10" 5 .10 2.5 .10 mide LG.30I40 N-ethyl-S-piperidyl 2-pheny1-2-hydroxy-cyclohexane-carboxylate LG.30141 diethylaminoethyl Z-phenyl-Z-hydroxy-cyclohexane-carboxylate 1.6.30144 2-diethylarninoethy1 Z-cyclohexyl-Z-hydroxy-cyclohexane-earboxylate LG.30127 2-(N-piperidino)-ethyl Z-phenyl-2-hydroxy-cyclohexanecarboxylate LG. 30128 3-diethylarnino-propyl 2-phenyl-Z-hydroxy-cyclohexanecarboxylate Buscopan N-butyl bromide ofjoscine Spasmamide diethylaminoethylamide of the monoethyl ester of phenylethyl-malonic acid The products according to the invention are much doperitoneal route in a 15 g. mouse (Swiss stock) is about 220 mg-kg (Papaverine LD 105 mg-kg).

Drugs according to the invention do not show hypotensive effects and are particularly suitable for spasms of biliary organs and the alimentary canal both because they are removed by the biliary tract and for their clearly anti-acetyl choline action, which action is of the same degree as that of stropine.

For these reasons the compounds of the present invention are therapeutic agents useful for treating many unhealthy conditions of biliary organs and liver, and in the therapy of spastic conditions of digestive organs, biliary organs, urinary organs and genital system.

The a following illustrates the production of antispastic compositions utilizing the compounds of the present invention as active ingredient.

Tablets weighing 0.1 g. each are prepared by normal tabletting procedures so that each tablet contains. 2-diethylaminoethyl 2phenyl-2- hydroxy-cyclohexane-carboxylate mg Starch 40 mg Lactose 30 mg Talc l5 mg Magnesium stearate 5 mg The normal dosage of the above tablets is 2 4 tablets per day.

The above tablets were utilized in clinical testing. The composition was tested on 42 subjects of both sexes, aged between and 60, divided into the followin g nosological groups according to disease:

Number of patients Spastic diseases of gastroenteric canal l6 Spasms of biliary organs l9 Spustic diseases of urological nature 4 Painful spastic manifestations of a gynecological relevancy 3 As diagnostic principles the subjective reports given by the subjects being examined and the objective reports provided by the ordinary research of physical and functional semeiology were used, and conformed to the following principle for estimating the therapeutic drug activity:

Remission of painful symptomatology after a period of time varying from 15 to minutes after supply, and improvement or resolution of instrumental or laboratory reports.

Patients suffering Results Total number of from: 0 patients Spastic diseases of gastroenteric canal 15 l 0 l6 Spasms of biliary organs l5 3 l [9 Spastic diseases of urological nature 2 0 2 4 Painful spastic manifestations of gynecological nature 1 l 1 3 It may be noticed from the results that maximum drug effectiveness was attained in spastic diseases of gastroenteric canal and biliary organs, where disappearance of troubles was noticed from the very first days of drug supply, while revealing a substantial improvement of digestive and hepatobiliary functionality. lnconstant results were achieved for uroligical and gynecological diseases. Perfect local and general tolerability in absence of secondary or atropino-wise effects was observed.

While the invention has been illustrated in particular with respect to certain specific esters, the production thereof, and the use thereof for their antispastic activity, it is apparent that variations and modifications of the invention can be made.

What is claimed is:

1. A compound selected from the group consisting of compowisis 9P 2jm a= it wherein R is selected from the group consisting of phenyl and cyclohexyl, and wherein X is COOR", whqrsia R7 s s ss sd fr mths g p nsistin of I C a WH 0 O I N N Ha zHa is 2-( N-piperidino)-ethyl 2-phenyI-2-hydroxy- 7. The compound of claim 1 wherein said conipound cyclohexane-carboxylate. H is 2-diethylamino-1l-l -methyl-ethyl 2-cyclohexyl-2- 6. The compound of claim 1 wherein said compound hydroxy-cyclohexane-carboxylate. is 3-diethylamino-propyl 2-phenyl 2hydgoxy a: a:

STAiES PATENT OEFICE CERTIFICATE OF CORRECTEON Patent No. 3 700 675 Dated Catcher 2Q 1,2 22

Inventor(5) Turbanti It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

[30] Foreign Application Priority Data April 29, 1966 Italy. 17,335

Signed and sealed this 8th day of May 1973.

(SEAL) Attest:

EDY'JARD I-i.FLETCHER,J'R. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents F ORM PO-1050 (10-69) USCOMM-DC 50376-P69- U.S, GOVERNMENT PRINTING OFFICE: I959 0-356-334 

2. The compound of claim 1 wherein said compound is N-ethyl-3-piperidyl 2-phenyl-2-hydroxy-cyclohexane-carboxylate.
 3. The compound of claim 1 wherein said compound is 2-diethylaminoethyl 2-phenyl-2-hydroxy-cyclohexane-carboxylate.
 4. The compound of claim 1 wherein said compound is 2-diethylaminoethyl 2-cyclohexyl-2-hydroxy-cyclohexane-carboxylate.
 5. The compound of claim 1 wherein said compound is 2-(N-piperidino)-ethyl 2-phenyl-2-hydroxy-cyclohexane-carboxylate.
 6. The compound of claim 1 wherein said compound is 3-diethylamino-propyl 2-phenyl-2-hydroxy-cyclohexane-carboxylate.
 7. The compound of claim 1 wherein said compound is 2-diethylamino-11-l -methyl-ethyl 2-cyclohexyl-2-hydroxy-cyclohexane-carboxylate. 